Efficacy, acceptability, and clinical effects of a low-dose injectable contraceptive combination of dihydroxyprogesterone acetophenide and estradiol enanthate.

A total of 1,904 women, aged 15-38, used an injectable contraceptive combination of 90 mg dihydroxyprogesterone acetophenide with 6 mg estradiol enanthate, given once during each menstrual cycle between the 7th and 10th day, and preferably on the 8th day of the cycle, for a total of 17,576 cycles. Of these 1,904 women, 1,197 completed 12 cycles of use of the injectable combination. One subject became pregnant during the trial, resulting in a cumulative pregnancy rate of 0.07%. Principal reasons for discontinuation were personal, non-medical reasons, such as lost to follow-up, no longer wished to continue, protocol violation, desire to change to another contraceptive method, moved away, or other personal reasons. Mean weight of 1,901 subjects at admission to the trial was 53.5 +/- 0.2 kg and this increased to 54.3 +/- 0.3 kg after 12 cycles of use. Approximately 50% of subjects experienced menstrual bleeding similar to normal throughout the study period. The most frequent menstrual abnormality was irregular bleeding, experienced by approximately one-third of subjects.

The effects of oral contraceptive use on iron and copper concentrations in breast milk.

OBJECTIVE: To determine the effects of oral contraceptive (OC) treatment on maternal iron and copper metabolism during lactation. DESIGN: Observational study. SETTING: Private and public clinics in Brazil. PATIENT(S): Lactating mothers attending the family planning clinic of the University of Brasilia. INTERVENTION(S): The OCs used were a combination pill (0.15 mg of levonorgestrel and 0.03 mg of ethinyl estradiol) and a minipill (0.35 mg of norethidrone). Blood and breast milk samples were collected before and after a measured period of OC treatment. MAIN OUTCOME MEASURE(S): Iron and copper concentrations were studied in the serum and breast milk of 54 breast-feeding mothers who had been advised by their physicians to use an OC, and in a control group. RESULT(S): Regression analysis was performed using a model that took into consideration socioeconomic status, number of children, duration of previous lactation, type of OC, length of treatment, and age. Repeated measurements (before and after OC treatment) showed that only copper concentrations in breast milk were significantly affected by stage of lactation. During the study period, which varied from 2-15 weeks, the decline in iron concentrations in breast milk was negligible, whereas copper concentrations decreased by 50%. CONCLUSION(S): The use of OCs does not appear to affect significantly the secretion of iron and copper in breast milk during the first 6 months of lactation.

PIP: This study examines the effects of oral contraceptive (OC) treatment on maternal iron and copper metabolism during lactation. The sample included lactating mothers attending the family planning clinic at the University of Brasilia. Participants were divided into 3 groups: 1) mothers who were taking combination pills (0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol); 2) those who were taking minipills (0.35 mg norethindrone); and 3) a control group. Blood and breast milk samples were collected before and after a measured period of OC treatment. Results showed no significant effects of OC use on either iron or copper concentrations in serum during lactation. However, copper concentrations were significantly affected with the stage of lactation (iron, P = 0.9619; copper, P = 0.0002) as reflected in the multivariate model analysis. Therefore, the use of OCs does not appear to affect significantly the secretion of iron and copper in breast milk during the first 6 months of lactation.

Multicenter, double-blind, comparative clinical study on the efficacy and acceptability of a monthly injectable contraceptive combination of 150 mg dihydroxyprogesterone acetophenide and 10 mg estradiol enanthate compared to a monthly injectable contraceptive combination of 90 mg dihydroxyprogesterone acetophenide and 6 mg estradiol enanthate.

Healthy, regularly menstruating women, aged 14-38 years, were enrolled in a comparative, double-blind, phase III, clinical trial to evaluate the contraceptive efficacy and acceptability of a combination of 90 mg dihydroxyprogesterone acetophenide with 6 mg estradiol enanthate compared to the commercially available contraceptive combination of 150 mg dihydroxyprogesterone acetophenide with 10 mg estradiol enanthate. Subjects received the contraceptive combination intramuscularly, between the 7th and 10th day of each menstrual cycle, during 12 consecutive menstrual cycles. Approximately 60% of the subjects in both groups completed the study. Principal reasons for discontinuation were personal, nonmedical reasons. Principal medical reasons for discontinuation were menstrual-related, irregular bleeding being the most frequent. Differences in menstrual patterns between the two groups did not lead to differences in discontinuation rates. Three contraceptive failures occurred during the trial, one in Group A (90/6 mg) and two in Group B (150/10 mg), indicating that the lower dose formulation is at least as efficient as the higher dose.

Self-administration with UniJect of the once-a-month injectable contraceptive Cyclofem.

The objective of this study was to evaluate women's acceptance of and ability to self-administrate the injectable contraceptive Cyclofem using prefilled UniJect devices. A total of 102 women were invited to participate in the study. Fourteen women (13.7%) refused to participate. Of the remaining 88 women, 32 women (31.4%) consented to participate and were trained using oranges but were still afraid of the procedure and ultimately refused to self-administer the injections. Only 56 women (55%) ultimately self-injected Cyclofem with UniJect. They performed a total of 144 injections, all of them on the ventral side of the thigh. When nurses evaluated women's ability to activate the devices, they found that more than 80% were successful in both the group of women that later self-administered the injections and the group that did not. The evaluation of the self-administered injection technique showed that more than 90% of the women correctly self-administered the contraceptive using UniJect. With respect to the opinion of the women about the self-administration of the contraceptive, more than 50% (32 of 56) of women who self-injected preferred to self-administer the injection and said that they wished to continue with the self-administration, one-third (17) reported that they were afraid, and seven women (12.5%) expressed the opinion that the injection in the thigh was more painful than the administration in the buttocks or arm. In conclusion, our study showed that women can be trained to successfully self-administer the monthly injectable contraceptive Cyclofem and generally respond positively to UniJect.

PIP: Women's capability to self-administer the monthly injectable contraceptive, Cyclofem, through use of prefilled UniJect devices was evaluated in 88 volunteers recruited from three Brazilian health clinics. After training in self-injection in which oranges were used for practice, only 56 of these women (55%) elected to continue with the study. They performed a total of 144 injections on the ventral side of the thigh. When nurses evaluated women's ability to activate the UniJect device, they found more than 80% of women trained in the method and 93% of those who actually performed self-injection used the technique correctly in an angle of 90 degrees. 32 (57.1%) of the 56 women who self-injected indicated they preferred this method and wished to continue to self-inject at home, another 17 (30.4%) reported they liked the method but were afraid to perform it on their own, and seven (12.5%) complained of pain associated with injection in the thigh compared with the buttocks or arm. Self-administration of injectable contraception, a popular method in Latin American countries, has the potential to increase contraceptive coverage as well as reduce costs associated with transportation to a source of contraception. If women are to perform self-injection at home rather than at a clinic, they will require reminders about the dates of reinjection and the importance of aseptic procedures and proper disposal of injecting equipment.

Hormonal treatment for bleeding irregularities in Norplant implant users.

OBJECTIVE: Our purpose was to evaluate whether prolonged or irregular bleeding during Norplant implant use could be alleviated with the use of oral hormonal medication. STUDY DESIGN: One hundred fifty users of the Norplant levonorgestrel contraceptive implant with prolonged or frequent bleeding were enrolled in this prospective, randomized, comparative study and assigned to one of three treatment groups for 20 days: ethinyl estradiol 50 microg, an oral contraceptive (50 microg ethinyl estradiol and 250 microg levonogestrel), and placebo. Total days of bleeding during treatment and length of the bleeding-free interval were analyzed. RESULTS: Women treated with the levonorgestrel-ethinyl estradiol pill bled an average of 2.6 days during treatment compared with 5.4 and 12.3 days in the ethinyl estradiol and placebo groups, respectively. Differences between both hormonal groups and placebo were significant (p <0.00001); moreover, the combined pill was more effective than ethinyl estradiol along (p <0.0001). CONCLUSION: The combined pill proved to be an excellent palliative treatment and is a more practical approach because of availability at all clinic sites.

PIP: In the Dominican Republic, clinical researchers randomly assigned 150 users of the contraceptive implant Norplant who came to Profamilia's Family Planning Clinic in Santo Domingo complaining of bleeding irregularities to one of three treatment groups. They aimed to evaluate the effectiveness of a combined oral contraceptive (OC) with 250 mcg levonorgestrel and 50 mcg ethinyl estradiol (EE) and of 50 mcg EE alone in treating bleeding irregularities. Bleeding irregularities were defined as prolonged bleeding (i.e., 8 or more continuous days of bleeding or spotting) or irregular bleeding (i.e., current bleeding episode initiated after a bleeding-free interval of less than 15 days). Age, parity, duration of Norplant use, and length of bleeding episode before treatment were similar in all three groups (i.e., OC, EE, and placebo). The OC group was significantly more likely to experience ceased bleeding within three days than the two other groups (91% vs. 67% for EE group [p 0.01 from OC group] and 15% for placebo group [p 0.0005 from both treatments]). Bleeding lasting for at least one week occurred less often in the OC group than the two other groups (2% vs. 14% for EE group and 50% for placebo group [p 0.0005 for both treatments]). Duration of bleeding was significantly lower in the OC group than the other two groups (2.6 days vs. 5.4 days for EE group and 12.3 days for placebo group; p 0.0001). Even though women in both hormonal treatment groups were more likely to experience gastralgia or nausea than the placebo group (33-40% vs. 4%; p 0.005), the side effects rarely interrupted treatment. These findings suggested that the OC is a very good effective treatment for bleeding irregularities and is a practical treatment since it is available at all Profamilia clinic sites.

Comparative study on intermittent versus continuous use of a contraceptive pill administered by vaginal route.

A multicenter, international, randomized, comparative trial was conducted to assess the acceptability, efficacy and safety of two different schedules of a contraceptive pill, containing 250 micrograms levonorgestrel and 50 micrograms ethinyl estradiol, administered by the vaginal route. One schedule of daily administration for 21 days with a seven-day interruption to allow withdrawal bleeding was compared to daily administration without interruption for bleeding. A total of 900 women were recruited in three countries, Brazil, Egypt and China; 7,090 women-months of vaginal pill use were recorded (3,364 using the pills intermittently and 3,726 continuously). Four undesired pregnancies occurred, one in Egypt and three in China, all four in women using the pills intermittently. There was a statistically significant difference (p = 0.486) in pregnancy rate between the two groups. There were no other significant differences in discontinuation rates despite marked differences in bleeding patterns, amenorrhea predominating in the continuous use group. Hemoglobin levels increased significantly in the two groups but hematocrit was significantly higher in the continuous use group.

PIP: 900 healthy women 16-42 years old were recruited in Brazil, China, and Egypt for a multicenter, randomized, comparative clinical trial to determine the acceptability, efficacy, and safety of two different schedules of a contraceptive pill with 250 mcg levonorgestrel and 50 mcg ethinyl estradiol administered vaginally. The two schedules were: 1) daily vaginal use of the pill for 21 days, followed by withdrawal for regular bleeding, and restarted 7 days later, and 2) use of the pill by the vaginal route nonstop for one year. There were no significant difference in cumulative discontinuation rates between the two groups (total, 15.5 for intermittent group and 14.64 for continuous group), except for unwanted pregnancy. The only unwanted pregnancies occurred to 4 women in the intermittent group (1.04%) (p = 0.0486). Women in the continuous use group were more likely than those in the intermittent group to have spotting at least once (20.6% vs. 4.4%; p 0.001). Women in the continuous group were more likely than those in the intermittent group to have amenorrhea. For example, the mean number of bleeding/spotting days during all time intervals was lower for the continuous group than for the intermittent group (p 0.001; last interval, 0.97 vs. 12.83). Hemoglobin levels increased considerably in both groups between baseline and one year of use (11.61 vs. 11.9 g/dl for intermittent group and 11.54 vs. 11.81 g/dl for continuous use; p 0.001). The mean value of hematocrit at 12 months for the continuous group was higher than that at baseline (38.8% vs. 38.2%; p = 0.011). It did not increase in the intermittent group, however. Women in both groups gained weight during the 12 months of pill use. The weight gain was significant for the continuous group only. These findings suggest that continuous use of vaginal contraceptive pills may be more advantageous than intermittent use oral contraceptives and may benefit anemic women and those who bleed heavily during menstruation.

[Estrogens. Contraceptive therapy]. / Estrógenos. Terapia anticonceptiva.

To evaluate the competitive molecular phenomenon of Ethynyl-Estradiol (EE-2) from contraceptive formulations against the endogenous Estradiol (E-2) at the intra and the extracellular compartments, plasma and endometrial samples were simultaneously obtained on different days of the pseudomenstrual cycle from oral contraceptive users under EE-2+ Norgestrel (30 micrograms/+ 500 micrograms) and EE-2+ Norethindrone (50 micrograms + 1.0 mg) in order to quantify EE-2 & E-2. When measuring both molecules it was shown that the chronic administration of steroids regardless of the pharmacological action of the progestin component the lower content of EE-2 (30 micrograms) does not compete substantially at the circulating level permitting the cyclic fashion of the natural estradiol while at the endometrial compartment such phenomenon is not seen thus, a local infertility effect should be reconsidered to anticipate a different approach in the future of contraception.

PIP: 27 women participated in a study of systemic and endometrial estradiol concentrations in oral contraceptive (OC) users. 13 women aged 15-22 used OCs containing ethinyl estradiol 30 mcg and norgestrel 500 mg for 4-24 months, and 14 women aged 18-28 used OCs containing 50 mcg ethinyl estradiol and 1.0 mg norethindrone for 1-28 months. A peripheral blood sample and an endometrial biopsy were obtained at random from each woman on different cycle days to measure the concentration of endogenous estradiol. The ovarian response defined by endogenous plasma and endometrial estrogen levels differed greatly in the two groups. In the 30 mcg group, plasma estrogen levels were similar to those described in an ovulatory menstrual cycle, while this profile was not observed in the 50 mcg group. The endometrial estrogen profile described for women not using hormonal contraception was not observed in either of the two dose groups.

Pharmacokinetics of once-a-month injectable contraceptives.

The addition of a short- or medium-acting estrogen ester to the long-acting progestins depot-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) to produce "combined" injectable formulations has proved a successful strategy in the development of once-a-month injectable contraceptives. Recent clinical pharmacokinetic studies undertaken on once-a-month injectable contraceptives in various WHO Collaborating Centers have guided the selection of the estrogen-progestogen combinations, ratios and dose schedules. At least three combined once-a-month injectable preparations exhibit acceptable pharmacokinetic and pharmacodynamic profiles; however, further improvement in the design of optimal estrogen/progestin injectables are expected during this decade.

PIP: The World Health Organization [WHO] Special Programme of Research, Development and Research Training in Human Reproduction has coordinated the developmental strategy of combined once-a-month injectable contraceptives. The strategy consists of the selection, based on pharmacokinetic data, of appropriate long-acting progestin-estrogen combinations to develop at least 2 sustained-release formulations; assessment of safety and effectiveness of these formulations in clinical research facilities; and their evaluation at field level through service facilities of national family planning programs. WHO Collaborating Centers were involved in selecting the estrogen-progestogen combinations, ratios, and dose schedules. Research has found at least 3 combined once-a-month injectable contraceptives that demonstrate acceptable pharmacokinetic and pharmacodynamic profiles. 2 safe and effective once-a-month contraceptive formulations (Cyclofem and Mesigyna) can join the existing choice of contraceptive methods. WHO expects more improvement in the design of optimal estrogen/progestin injectables in the 1990s.

Comparative study on the efficacy, acceptability, and side effects of a contraceptive pill administered by the oral and the vaginal route: an international multicenter clinical trial.

The objective of this multicenter randomized clinical trial was to compare the efficacy, acceptability, and occurrence of side effects associated with the oral versus vaginal route of administration of contraceptive pills. Eight hundred nineteen healthy, parous women of reproductive age were recruited at family planning clinics and research centers, members of the South to South Cooperation in Reproductive Health, in seven countries of the developing world. These women were randomly assigned to use either oral or vaginal administration of the same contraceptive pill, which contained 250 micrograms levonorgestrel and 50 micrograms ethinyl estradiol. No statistically significant differences were found in discontinuation rates between the two groups after 1 year. Involuntary pregnancy rates after 1 year were not statistically significantly different between the two groups. The vaginal route of administration appears to be as acceptable and efficacious as the oral route.

PIP: The objective of this multicenter randomized clinical trail was to compare the efficacy, acceptability, and occurrence of side effects associated with the oral versus vaginal route of administration of contraceptive pills. This study started in June, 1987, and data collection extended up to April, 1992, at family planning clinics and research centers, members of the South to South Cooperation in Reproductive Health, in seven countries of the developing world. The 819 subjects were from 17 to 39 years of age, had already had at least one pregnancy, had had regular menstrual cycles for 3 months before, were exposed to the risk of pregnancy, and were not using any other method of contraception. 424 were randomly assigned to use the pills orally (which contained 250 mcg levonorgestrel and 50 mcg ethinyl estradiol), whereas 395 inserted the pills vaginally. 625 subjects completed at least 6 months of use, 326 used the pills orally and 299 used the pills vaginally. 385 subjects completed 1 year of pills use, 201 in the oral group and 184 in the vaginal group. The 1-year discontinuation rate per 100 subjects per year for the oral group was 34.71 +or- 2.42, while it was 36.35 +or- 2.53 for the vaginal group. This difference was not statistically significant. The only single reason of statistically significant difference for discontinuation was "desire for pregnancy" (p = 0.444). Paired value analysis of subjects completing 12 months of study showed that women in the oral group had a statistically significant increase in weight, from a mean of 55.8 kg at admission to a mean of 56.9 kg at 6 months (p 0.05) and 57.3 kg at 1 year (p = 0.05). The mean weight of the vaginal group increased from 56.52 kg to 57.22 kg (p = 0.036) at 12 months. Significantly more complaints of vaginal discharge were recorded in women using the pills by the vaginal route (p = 0.001). However, only one subject discontinued the pills because of vaginal discharge.

Comparative study on the efficacy and acceptability of two contraceptive pills administered by the vaginal route: an international multicenter clinical trial.

The efficacy and acceptability of two widely used oral contraceptive tablets, one containing 250 mg levonorgestrel and 50 micrograms ethinyl estradiol and the other containing 150 micrograms desogestrel and 30 micrograms ethinyl estradiol, administered by the vaginal route were compared in 1055 women studied over 12,630 woman-months of vaginal contraceptive pill use. This multicenter clinical trial was performed in nine countries of the developing world by the "South to South Cooperation in Reproductive Health," an organization founded by scientists from the Third World working in the area of reproductive health, and the study was developed and coordinated by one of these centers. The findings of this study confirm the efficacy of both these tablets when administered by the vaginal route. Involuntary pregnancy rates at 1 year of 2.78 for subjects in the levonorgestrel group and 4.54 for subjects the desogestrel group showed no statistically significant difference between the two groups. However, total discontinuation rates of 47.01 for subjects in the levonorgestrel group and 56.33 for subjects in the desogestrel group showed a statistically significant difference between the two groups, and discontinuation rates attributable to prolonged bleeding of 0.6 for subjects in the levonorgestrel group and 3.2 for subjects in the desogestrel group were also significantly higher in the group of subjects using the desogestrel vaginal contraceptive pill. Blood pressure remained at admission values throughout treatment. A statistically significant weight increase from admission values occurred in both groups of subjects.

PIP: Efficacy and acceptability of 2 combined oral contraceptive pills administered vaginally are summarized. This is the 1st collaborative trial published by the South to South Cooperation in Reproductive Health. 1055 women participated in 12,630 cycles, in 9 countries, from June 1988 to May 1991. The pills were commercially available tablets containing 50 mcg ethinyl estradiol and 250 mg levonorgestrel (Schering AG, Sao Paulo, Brazil), or 30 mcg ethinyl estradiol and 15 mcg desogestrel (Organon, Sao Paulo, Brazil). Subjects were aged 17-39 younger and of lower parity from Mexico and Dominican Republic and older from Egypt and China. All had at least 1 pregnancy. 675 participated for 6 months, 470 for 1 year, 364 for 18 months, and 210 for 2 years. The 1-year discontinuation rate averaged 47.01% for the levonorgestrel group and 56.33% for the desogestrel group (p = 0.0061); 2-year discontinuation rates were 48.01% and 69.36, respectively, explained in part by higher involuntary pregnancy rates and prolonged bleeding rates in the desogestrel group. The most common medical reasons for stopping contraception were unplanned pregnancy, vaginal or vulval irritation, nausea, vaginal discharge and headache. Vaginal irritation was reported by 1%, 9 in each group. There were 32 pregnancies, 14 in the levonorgestrel and 18 in the desogestrel group. 17 were in missed pill cycles and the rest were method failures, 6 in the levonorgestrel group and 9 in the desogestrel group. The Pearl index varied from 0 in Nigeria to 12.24 in Mexico, and was 2.45 for levonorgestrel vs. 3.74 for desogestrel. There was a wide variation in discontinuation rates by center: Brazil and China had few, while many women from Dominican Republic, Mexico and Zambia left the study. Bleeding problems were common complaints, more so in the desogestrel group. There were 363 women with intermenstrual bleeding (only once in 80%), 148 with spotting (only twice in 65%). Bleeding duration was significantly less in pill cycles than baseline, pressure. Women gained an average of 1 kg over 2 years, more in the desogestrel group. The pregnancy rate of 2.78 is within the range reported for levonorgestrel rings.

Evaluation of four different contraceptive vaginal rings: steroid serum levels, luteal activity, bleeding control and lipid profiles.

Four different models of contraceptive vaginal rings were tested during three cycles for luteal activity, bleeding control, plasma lipoproteins and serum levels of the contraceptive steroids. Two progestins, levonorgestrel acetate (LNGA) and ST 1435, alone or in combination with ethynyl-estradiol (EE) were tested. The rings released 100 ug/day of the progestins and 30 ug/day of EE. Luteal activity was detected among users of the progestin-only rings: 4 of 8 cycles with ST 1435 and 2 of 10 with LNGA. Only one of the 18 cycles studied with the two combined rings showed luteal activity, but the measurement of contraceptive steroid in plasma suggested that this subject delayed reinsertion of the ring for about one week in that particular cycle. Breakthrough bleeding was observed in 12 of 30 cycles of use of the progestin-only rings, and in only 2 of 27 cycles with the combined models. No significant changes in total cholesterol or its HDL-fraction were observed. However, the only reduction observed in HDL-cholesterol was among users of the LNGA-only ring. It is concluded that the two combined CVR models offer good possibilities of high effectiveness and bleeding control and merit further development.

PIP: Researchers analyzed data on 20 18-38 year old volunteers from the family planning clinic of PROFAMILIA in Santo Domingo, Dominican Republic, who had earlier undergone female sterilization to evaluate 4 different models of contraceptive vaginal rings during 3 cycles so as to identify which models would be the most likely to be an acceptable, safe, and effective family planning method. Women who used either of the 2 combined rings (ethinyl estradiol [EE] and either levonorgestrel acetate [LNGA] or ST 1435) had higher mean total serum levonorgestrel levels than those using the progestin-only rings (LNGA or ST 1435) (most were significant at .005). Luteal activity which marked ovulation was basically limited to users of the progestin-only rings (50% of cycles with ST 1435 and 20% of LNGA). It occurred in 1 of 18 cycles (5.6%) of users of combined rings (LNGA + EE). It probably occurred because of delayed insertion. The combined rings caused fewer incidents of breakthrough bleeding than did the progestin-only rings (7.4% vs. 40%). Neither the progestin-only nor the combined vaginal rings significantly altered total cholesterol or high density lipoprotein (HDL) levels. Users of the LNGA-only ring did experience an insignificant reduction in HDL, however. Further, triglycerides increased among users of the combined vaginal rings, but the increase was only significant with the LNGA + EE ring (25.4 mg/dl increase; p .05). Moreover, they fell significantly among users of the LNGA only ring (45.5 mg/dl decrease; p .05). The researchers concluded that the 2 combined rings hold the most promise due to good bleeding control and high effectiveness and therefore deserve further development.

Desogestrel-ethinylestradiol, an oral monophasic contraceptive. Clinical and lipid metabolic effects: a 5-year experience.

A comparative study of 5 years' duration using desogestrel (DSG), levonorgestrel (LN), and norethindrone (NET), combined with ethinyl estradiol (EE), was conducted. A total of 4499 cycles on DSG-EE, 3691 on LN-EE (1980 on triphasic and 1711 on monophasic schemes) and 1680 on NET-EE was evaluated. A contraceptive efficacy of 100% was obtained in all the groups. Minimal side effects were observed. In particular, body weight in those women on DSG-EE did not show noticeable changes and headaches were minimal. No alterations on blood pressure readings or on the routine laboratory tests were noticed in any of the groups. There was a significant increase in high-density lipoprotein-c (HDL-c) in women on DSG-EE. There was no change in NET-EE, and a significant decrease in women on LN-EE in both schemes. Changes in LDL-C, very low density lipoproteins, triglycerides, total lipids, total cholesterol, and glucose were not significant, although there was some increase at 60 cycles on triglycerides on those women on DSG-EE and on NET-EE. At the end of 5 years, 76% of women continued on DSG-EE. They indicated their satisfaction with this method.

Long-acting hormonal contraceptives for women.

Following the development and widespread use of oral hormonal contraceptives, it became evident that alternative long-acting delivery systems would be required to improve contraceptive practice in some cultural settings where injectable or subdermal routes of administration are preferred. Nowadays, long-acting contraceptives constitute an important option in family planning services in many parts of the world. Indeed, two long-acting injectable contraceptives containing just a synthetic progestogen (depot-medroxyprogesterone acetate (DMPA) and norethisterone enantate (NET-EN)) have been in clinical practice for more than 20 years. The World Health Organization's (WHO) Special Programme of Research in Human Reproduction, in collaboration with the U.S. National Institute of Child Health and Human Development (NICHD) and universities primarily in developing countries undertook a synthesis programme aimed at producing an improved injectable preparation by developing new derivatives of known steroids. One such compound (levonorgestrel 17-butanoate) is now at the stage of Phase II clinical testing. In addition, the Special Programme has developed and improved once-a-month injectable formulations and assessed their safety and efficacy in different countries worldwide. After large scale clinical testing, at least two progestogen-estrogen combinations have reached the point of introductory trials.

PIP: A survey of recent trials of new injectable hormonal contraceptives, progestogen-only, levonorgestrel esters, and once monthly injectables, follows a brief review of all the experimental long-acting contraceptive modalities, injectables, implants, vaginal rings, and hormone-releasing IUDs. Currently medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) are being used by 7 million women. WHO is conducting dose reduction trials and studies of bioavailability in various national populations. Even though a dose of 100 mg DMPA every 3 months has been satisfactory for contraception, 150 mg is still recommended until further pharmacodynamic data are available. Some populations, notably Thais and Mexican women, have higher peaks and more rapid elimination rates of DMPA, while Chinese women show slower elimination and higher blood levels of NET-EN. Extensive studies of new synthetic esters of levonorgestrel have proceeded to Phase II clinical trials with levonorgestrel butanoate. This ester is an effective contraceptive for 3 months at 12.5 mg, or 5-6 months at a dose of 25 or 50 mg. Trials of combined estrogen and progestogen injectables once-monthly have been ongoing for 10 years. The ratio of the 2 components is as important as the amounts. 2328 women from 12 countries participated in trials of DMPA 25 mg-estradiol cypionate 5 mg, and NET-EN 50 mg-estradiol valerate 5 mg. The continuation rate was better than that for 3-monthly progestogen-only injectables, because of less irregular bleeding. A combined injectable called Cyclofem, DMPA 25 mg-estradiol cypionate is being introduced in several countries. The steadily increasing demand for long-acting injectables prompts development of better formulations.

[Pharmacodynamics of synthetic estrogens. Review article]. / Farmacodinámica de los estrógenos sintéticos. Artículo de revisión.

Some details about the function of natural and synthetical hormonas are reviewed, particularly estrogens as ethynyl estradiol and its 3, Methyl ether (mestranol); its peripheral concentration vs tissular hormonal contents, a relationship of biological importance as the first step in its hormonal action and the cummulative local effects that could explain some intra and extracellular phenomena.

PIP: Some studies of the peripheral concentration and concentration in reproductive tissues of ethinyl estradiol (EE) and mestranol are reviewed. Orally administered EE is observable in the peripheral circulation within 30-60 minutes. A 1970 study of radioactive EE demonstrated that the endometrium and ovaries captured most of the EE, with levels in the uterus and serum much lower. Adipose tissue was found to be important in storing the hormones. Other studies of radioactive mestranol and EE demonstrated that the compounds were deposited in other organs in significant quantities and that the deposits were perhaps irreversible or of very slow release. The ability of estrogens to remain concentrated at the systemic level and not just in reproductive organs may be related to some adverse effects reported in women using oral contraceptives (OCs). Advances in radiochemistry and immunology in the 1960s made it possible to measure steroid hormone levels in different tissues. The capacity of the endometrium to concentrate natural steroids such as 17-beta estradiol and progesterone during the ovulatory menstrual cycle was demonstrated in 1978. A subsequent study showed that the endometrium captured and stored the synthetic estrogen EE in even greater concentrations than the natural estrogen estradiol. A study of the pharmacodynamics of EE in hysterectomized women showed that 24 hours after the 1st dose of 30 mcg the EE was not detected in the peripheral circulation. But the peripheral concentration increased with continuous daily administration of 30 mcg of EE. 27 days after suppression of treatment it was still detectable in the peripheral circulation. Another experiment was designed to measure simultaneously the concentrations of EE in the peripheral circulation and in the endometrial tissue of 36 women terminating use of OCs containing norgestrel and EE after 2-36 months of treatment. The study showed that synthetic estrogen was still observable in the endometrial tissue 1 month after discontinuing OC use. Inexplicably, levels of EE were higher in the circulation in the cycle after treatment than in the final treatment cycle. 5 of the women participated in the study for 3 posttreatment cycles. EE was observed in the circulation 1 month after termination of OC use in 5 women, 2 months after termination in 4 women, and 3 months after termination in 3 women. The persistence of EE in the tissue months after termination of treatment suggests the need for further research and assessment of possible resulting risks.

A clinical overview of a new triphasic contraceptive containing gestodene.

In three ongoing open studies conducted by 50 investigators in Europe, South America, and New Zealand, 639 subjects followed a new triphasic regimen of gestodene (GTD) and ethinyl estradiol (EE) for 3,020 cycles. One study used GTD + EE only, but in each of the other two studies a comparator oral contraceptive (OC) also was given: norethisterone (NET) + EE in one and desogestrel (DSG) + EE in the other. The objective of all three studies was to assess the efficacy, cycle control, and safety of the triphasic GTD + EE. The following is a report of the interim results. Statistical analysis was performed only on differences between groups in the incidences of bleeding irregularities. During six treatment cycles, subjects either followed the GTD + EE regimen (50 micrograms GTD + 30 micrograms EE for 6 days, 70 micrograms GTD + 40 micrograms EE for 5 days, and 100 micrograms GTD + 30 micrograms EE for 10 days) or took triphasic NET + EE or monophasic DSG + EE. Each cycle concluded with a seven-day hiatus in study medication. No pregnancies occurred with any of the contraceptive preparations (Pearl Index = 0). Compliance was good in all studies and a majority of subjects were still participants at cycle 6. Normal bleeding was reported during 92% of the total evaluable cycles of GTD + EE use. Cycle control with GTD + EE was superior to that with NET + EE or DSG + EE: Breakthrough bleeding occurred in 1.5% of the pooled GTD + EE cycles versus 6.6% of the NET + EE cycles and 2.6% of the DSG + EE cycles; spotting occurred in 4.5% of the GTD + EE cycles versus 9.7% of the NET + EE cycles and 10.3% of the DSG + EE cycles; and breakthrough bleeding plus spotting occurred in 2.1% of the GTD + EE cycles versus 8.1% of the NET + EE cycles and 4.6% of the DSG + EE cycles. Amenorrhea occurred in 2.0% of the cycles with NET + EE, but was reported by only 0.3% of all the subjects given GTD + EE and 0.7% of those given DSG + EE. Cycle length and intensity of bleeding changed little during the use of any of the study preparations. Mean length of withdrawal bleeding during the GTD + EE regimen shortened from 4.5 days (prestudy) to 4.0 days. With each OC, the subjects' mean weight during cycles 3 and 6 differed less than 0.5 kg from baseline values.(ABSTRACT TRUNCATED AT 400 WORDS)

A comparison of a new graduated estrogen formulation with three constant-dosed oral contraceptives.

Four-hundred-twenty-six women, aged 18 to 36, completed a four-cycle comparative, randomized, single-blind (observer blind), multicenter study of a new graduated estrogen formulation with three constant-dosed combination oral contraceptives containing the same synthetic steroid compounds. The products studied were Loestrin 1/20, Loestrin 1.5/30, Norlestrin 1/50, and a new graduated estrogen product, Estrostep. A total of 1,850 cycles were completed and analyzed for efficacy, side effects, metabolic changes, and cycle control. Four pregnancies occurred during the course of the study. None of the pregnancies occurred in the group receiving Estrostep. The new formulation produced the lowest rate of breakthrough bleeding (BTB) compared with the other three products. All four combination oral contraceptives resulted in an increase in high-density lipoprotein cholesterol (HDL-C). The levels of HDL-C were greatest with Estrostep.

[Oral contraceptives and metabolic changes]. / Anticonceptivos orales y alteraciones metabólicas.

PIP: Sufficient evidence has accumulated to relate oral contraceptives (OCs) to various cardiovascular diseases in which metabolic alterations play a role. Although epidemiological studies have shown OC users to be at greater risk of venous thrombosis than nonusers, blood coagulation studies of OC users have yielded conflicting results due to variations in the methodologies used, the factors studied, the different formulations and doses of OCs, and the duration of use. Moreover, no satisfactory method exists of measuring coagulability in its totality, which is the sum of the effects of individual variations in coagulation factors, fibrinolysis, and platelet function. Numerous studies have shown that OC users have increased levels of several coagulation factors, which are believed to indicate hypercoagulability and increased risk of thrombosis, but the pathogenesis of venous thrombosis is complex. Accompanying changes in the fibrinolytic system can be interpreted as attempts to equilibrate the hypercoagulability induced by OCs. Further, there is no proof that in vitro changes are related to thrombosis in vivo. The alterations appear to be dose-related, produced primarily by estrogens, unrelated to duration of use, and to disappear a few months after termination of OC use. OC users have been shown repeatedly to have elevated levels of glucose and insulin, which are especially pronounced in glucose tolerance tests. The changes vary in intensity according to the dose and progestational components and the existence of other risk factors for diabetes. Deterioration of glucose tolerance appears related to duration of OC use, but serum insulin levels maintain the same initial elevations. The estrogens have been shown to have few effects on carbohydrate metabolism in the lower doses currently used. Norgestrel has the most marked effects on glucose and insulin levels, ethynodiol diacetate has moderate effects, and norethindrone has the least effect. The combination of .15 mg levonorgestrel and 30 mcg ethinyl estradiol has no effect on oral glucose tolerance and little effect on insulin secretion. It is hypothesized that OCs affect carbohydrate metabolism by decreasing the number and affinity of insulin receptors in target tissues. The mechanisms by which OCs produce undesirable effects on the cardiovascular system are not completely understood, but are believed to be related to alterations in lipid metabolism. The majority of laboratory studies have shown that OC users had elevated levels of cholesterol, triglycerides, and the (LDL) fractions, and a diminution of the high density lipoprotein (HDL) fraction, which has antiatherogenic properties. The changes are atherogenic in nature and produce a lipid profile similar to that of men and postmenopausal women, who are at greater risk of thrombotic cardiovascular disease that premenopausal women who are protected by estrogens. .^ieng

[Oral contraceptives and cardiovascular diseases morbidity]. / Anticonceptivos orales y morbilidad de enfermedades cardiovasculares.

PIP: A case control study was conducted in Mexican Institute of Social Security hospitals in the Valley of Mexico to determine the relationship between oral contraceptive (OC) use and nonrheumatic cardiovascular disease in Mexican women. The study involved Mexican women between 20-44 years of age residing in the metropolitan Mexico City area and married or in stable union. 28 women hospitalized with confirmed diagnoses of ischemic heart disease, 22 with cerebrovascular accidents, 70 with pulmonary embolism or venous thrombosis, 33 with hypertensive cardiopathy, and 55 with other nonrheumatic heart diseases comprised the 201 cases. The 606 controls were women hospitalized with noncardiovascular acute illnesses who met the same requirements for inclusion or exclusion as the cases. Over 98% of the women in the study had been pregnant at some time. OC users were younger and better educated than nonusers. 30% of OC users and 26% of nonusers were smokers. The relative risk of nonrheumatic cardiovascular disease was 1.22 for past users of OCs, who included women using OCs until 1 month prior to the interview. The relative risk for women using OCs within 30 days of the interview (current users) was 1.24. The relative risk according to the estrogen dose was 1.79 for users receiving 40 mcg or less, but paradoxically doses of over 40 mcg decreased the risk to .75. The risk was 1.35 after 1 year of use of OCs, .96 from 12-18 months of use, and 1.34 after 48 months of use. The relative risk was .95 for ever users of OCs aged 20-29 years, 1.38 for those aged 30-39, and 1.48 for those 40-44. Among current users the relative risks were 1.19 for those aged 20-29, .84 for those aged 30-39, and 3.83 for those aged 40-44. The relative risks for ever users and current users respectively were 1.65 and 2.01 for ischemic heart disease and cerebral vascular accidents; 1.40 and 1.43 for pulmonary embolism and venous thrombosis; .85 and .71 for hypertensive cardiopathy; and 1.09 and 1.91 for other cardiovascular diseases. Users and nonusers of OCs had the same access to medical services. Observed differences in the ages and educational levels of users and nonusers were not a source of bias because cases and controls were paired by age and education. The results demonstrated that Mexican women in the Valley of Mexico who use OCs have a statistically significant elevated risk of developing nonrheumatic cardiovascular disease. In declining order of risk are cerebral vascular accident, ischemic heart disease, and pulmonary embolism and venous thrombosis. The risk is present from the 1st days of OC use and in use of OCs containing less than 40 mcg of estrogen. The risk increases with the age of users but not with smoking.^ieng

[A new ovulation inhibitor antiandrogen]. / Un nuevo anovulador antiandrogenico.

PIP: Cyproterone acetate (Androcur), a potent progestagin and antigonadotropin, has been widely used in Europe in treatment of hirsutism, seborrhea, and alopecia. A formulation combining an estrogen, ethinyl estradiol (EE), to neutralize the progestational action and consequent amenorrhea of Androcur is marketed under the name of DIANE. 3 different treatment protocols were tested: 1) continuous administration of Androcur at doses varying from 25-150 mgr with rests every 3 months 2) high dose combination of 50 mgr Androcur and .05 mgr of EE in 21 day cycles and 3) low dose combinations of 2 mgr Androcur and .05 mgr of EE in 21-day cycles (DIANE). 54 patients who received the DIANE combined low dose treatment were compared. 7 of them had previously received the cyproterone acetate in variable doses of 25-150 mgr/day for 3-10 cycles, 16 had previously taken cyproterone acetate in variable doses of 50-150 mgr/day for 3-14 cycles, followed by the high dose combined method for 3-12 cycles and DIANE for 1-7 cycles, and 15 patients had previously received the high dose combined method for 2-22 cycles followed by DIANE for 3-7 cycles. Among the 54 patients there were 10 cases of idiopathic hirsutism, 11 of suprarenal hirsutism, 25 of ovarian hirsutism, 2 of iatrogenic hirsutism, 24 of acne, 37 of seborrhea, and 10 of alopecia. No pregnancies were reported in patients exposed to risk of pregnancy who took a total of 96 cycles of DIANE or 55 cycles of the high dose combination. Continuous dose cyproterone acetate is usually associated with amenorrhea. The high dose combination induces amenorrhea in up to 20% of cases, while with DIANE the principal change is a diminution in the amount of bleeding. Cyproterone acetate alone or associated with androgens is the preferred treatment for androgenic manifestations. The therapeutic regimen should be adapted to the predominance, time of evolution and severity of symptoms. For moderate or serious hirsutism, the treatment should be continuous administration of high doses of cyproterone acetate for 6 months followed by the combined method at high doses according to the type of initial response. When acne and seborrhea predominate, the combined low-dose method is used, because even though the high dose continuous method gives better results, the secondary effects do not justify its use. The high dose continuous method can be chosen if the low dose combined method fails. The high dose combined method is preferred for alopecia, with the low dose combined method used for maintenance.^ieng

[A ten year clinical investigation of injectable contraceptives]. / Investigacion clinica sobre diez anos de anticonceppion inyectable mensual.

PIP: The article describes the results obtained over a period of 10 years with contraception by monthly injection of 150 mg of dihydroxyprogesterone acetophenide, and 10 mg of estradiol enanthate. 100 fertile patients were observed, for a total of 8074 cycles. There were no pregnancies, and only minimal side effects. No changes were observed in blood profile, urine and hepatic function, and in blood coagulation; there were no instances of breast or uterine cancer. In 10 years only 15% of patients abandoned this method because of changes in the menstrual cycle, changes which were expected, but which had not been explained to the patients.^ieng